Entecavir, [1-S-(1α,3α,4β)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one, is currently used for treating hepatitis B virus infection, whose structure is composed of a cyclopentane ring having purine, exomethylene, hydroxymethyl, and hydroxy substituents at the 1S-, 2-, 3R-, and 4S-positions, respectively.
There have been conducted a number of studies to develop methods for preparing entecavir. For example, U.S. Pat. No. 5,206,244 and WO 98/09964 disclose a method for preparing entecavir as shown in Reaction Scheme 1:

wherein P1 is trityl or substituted trityl, Bn is benzyl, BOMCP is benzyloxymethylcyclopentadiene, IpcBH is diisopinocampheylborane, DMAP is N,N-dimethyl-4-aminopyridine, DMF is dimethylformamide, MC is methylene chloride, MMTr-Cl is 4-monomethoxytrityl chloride, TBAI is tetrabutylammonium iodide, TEA is triethylamine, and THF is tetrahydrofurane.
The above method, however, has difficulties in that: i) the cyclopentadiene monomer must be maintained at a temperature lower than −30° C. in order to prevent its conversion to dicyclopentadiene; ii) residual sodium after the reaction as well as the sensitivity of the reaction toward moisture cause problems; iii) the process to obtain the intermediate of formula (1a) must be carried out at an extremely low temperature of below −70° C. in order to prevent the generation of isomers; iv) a decantation method is required when (−)-Ipc2BH (diisopinocampheylborane) is used for hydroboration; v) the process for preparing the intermediate of formula (1e) does not proceed smoothly; and, vi) separation by column chromatography using MCI GEL™ CHP-20P resin (Sigma-Aldrich) is required to purify entecavir.
WO 2004/52310 and U.S. Pat. Publication No. 2005/0272932 disclose a method for preparing entecavir using the intermediate of formula (2f) which is prepared as shown in Reaction Scheme 2:

wherein, Me is methyl, t-Bu is t-butyl, Et is ethyl, n-Hex is n-hexane and Ph is phenyl.
The above method for preparing the intermediate of formula (2b) must be carried out at an extremely low temperature of −70° C. or less, and the yield of the desired product (2f) in the optical resolution step is less than 50%.
Various methods for preparing triflic enolate have been developed. For example, the document [“Preparation of allylsilane 12”, J. Am. Chem. Soc., 1998, 120, 12980-12981] has disclosed a method for preparing triflic enolate comprising the step of conducting regioselective reaction of potassium hexamethyl disilazane (KHMDS) with N-phenyl triflimide (PhNTf2) as described in reaction scheme 3. U.S. Pat. No. 7,381,746 B2 has disclosed a method for preparing triflic enolate as described in reaction scheme 4. The document [J. Chem. Soc., Perkis Trans. 1, 2000, 345-351] has also disclosed a method for preparing triflic enolate.


wherein R is a hydroxy protecting group, X is halogen or benzyloxy, MOP is 2-methoxy-2-propyl ether, TBS is t-butyldimethylsilyl, Tf is trifluoromethansulfonyl, and TMS is trimethylsilyl.
In the above methods for preparing triflic enolate, the process to obtain triflic enolate must be carried out at an extremely low temperature over a long period of reaction time, and the process to obtain triflic enolate disclosed in U.S. Pat. No. 7,381,746 B2 also was carried out at the temperature of −63° C. to −45° C. However, the starting material used for preparing triflic enolate undergoes easy decomposition at a temperature above −30° C., which is not suitable for mass production of triflic enolate.